New study analyses global trends in pregnancy loss, provides 10-year forecast and identifies a range of risk factors
The most comprehensive and up-to-date study of the global burden of pregnancy loss has analysed trends in pregnancy loss across more than 200 countries, provided a 10-year forecast and identified a range of risk factors.(1)
The incidence of pregnancy loss has trended downwards globally during the last 30 years and is predicted to decline further by 2030.
Sedentary behaviour, smoking and poor health may be ‘powerful indicators’ of an increased risk – while an increase in educational levels and maternal birth weights may, in time, help reduce the burden of pregnancy loss, say the study’s authors.
Pregnancy loss has high healthcare and social costs and can put a physical and psychological strain on women.
A better understanding of how the incidence of pregnancy loss varies around the world and of the factors that affect the risk of pregnancy loss can aid in the design of interventions and help reduce the burden in future.
To this end, the authors first used data from the Global Burden of Disease 2019 study (GBD 2019), which includes information from sources such as censuses, medical registries and demographic surveillance, to provide an overview of trends in pregnancy loss from 204 different countries and 21 regions from 1990 to 2019.(2)
Pregnancy loss, defined as loss of an embryo before it comes viable, was identified from the International Classification of Diseases 9th Revision (ICD-9) and 10th Revision (ICD-10) codes in the GBD 2019, and includes all intrauterine pregnancies.(2)
The results show there were approximately 42.39 million cases of pregnancy loss worldwide in 2019.
Incidence (-14.6%), disability life-adjusted years (DALYs, -67.2%), maternal mortality (-67.1%), age-standardised incident rate (ASIR, -1.44%), age-standardised rate of DALYs (ASDR, -5.21%) and age-standardised mortality rate (ASMR, -5.14%) showed a decreasing trend in all socio-demographic index regions (SDI, an indicator of regional development), with high SDI regions showing the largest decline.
The highest ASIR in 2019 was in Ethiopia; Chad had the highest ASDR and ASMR. Central Europe was the only region to show an increase in the number of pregnancy losses over the past 30 years.
Pregnancy loss-related mortality increased with age, peaking at 40-44 years in 2019. This, together with the high number of DALYs in the 35-44 years age group, implies the need to strengthen healthcare policies for pregnancies in women aged over 35 years, say the authors.
Next, the authors used the autoregressive integrated moving average (ARIMA) model to provide a 10-year forecast. This predicted that age-standardised incidence, DALYs and mortality rate will continue to decrease between 2020 and 2030, although the decrease in ASDR and ASMR will gradually slow down. This, say the authors, emphasises the need for policymakers to focus on post-natal treatment and management.
Finally, the study explored risk factors for pregnancy loss. Previous observational studies have identified a range of risk factors but the conclusions are inconsistent and may be biased by residual confounders.
Mendelian randomisation (MR), an approach that minimises reverse causation and confounding biases, was used to address this. Data on 33,239 pregnancy loss and 89,340 non-pregnancy loss cases from the FinnGen consortium, a public-private partnership in Finland, were used to investigate the effect of 15 factors on the risk of pregnancy loss.(3)
Five factors were found to be significantly associated with pregnancy loss. These were as follows: overall health rating (odds ratio (OR)1.68, 95% CI 1.34–2.13), smoking initiation (OR 1.26, 95% CI 1.16–1.38), sedentary behaviour (OR 1.56, 95% CI 1.20–2.01), educational level (OR 0.64, 95% CI 0.55–0.73) and maternal birth weight (OR 0.70, 95% CI 0.58–0.85).
Another four factors showed weaker correlations with pregnancy loss: body mass index (OR 1.10, 95% CI 1.03–1.17), alcohol consumption (OR 1.74. 95% CI 1.03–2.95), insomnia (OR 1.66, 95% CI 1.14–2.42), and moderate-to-vigorous physical activity (MVPA, OR 0.59, 95% CI 0.37–0.95). All associations were shown using at least two MR methods. Results detailed here are from the inverse variance weighted median (IVW) method.
Caffeine intake (from tea and coffee), alcohol frequency, daily naps, snoring and vigorous physical activity were not associated with pregnancy loss.
The authors acknowledge that the MR study was limited to a European population and so the findings on risk factors may not apply more widely.
Moreover, despite their efforts to standardise data from all over the world, some uncertainties in data quality control remain. This includes different countries using different gestational ages or foetal weights in their definition of pregnancy and the potential underestimation of the burden of pregnancy loss in countries with low levels of medical care.
The authors conclude: “Smoking, overall poorer health condition and sedentary behaviour may be powerful indicators of an increased risk of pregnancy loss.
“An increase in educational levels and birth weights may eventually reduce the risk of pregnancy loss, while there is support for causal roles of obesity alcohol consumption and insomnia in increasing pregnancy loss and for MVPA in reducing pregnancy loss.
“Our findings may provide directions for public health interventions and clinical strategies to prevent pregnancy loss.”
1.Tong F, Wang Y, Gao Q, Zhao Y, Zhang X, Li B, et al. The epidemiology of pregnancy loss: global burden, variable risk factors, and predictions. Human Reproduction. 2024 Feb 2. doi.org/10.1093/humrep/deae008
2. Vos T, Lim SS, Abbafati C, Abbas KM, Abbasi M, Abbasifard M, et al. Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019. The Lancet. 2020 Oct 17;396(10258):1204–22. doi.org/10.1016/S0140-6736(20)30925-9 3. Kurki, M.I., Karjalainen, J., Palta, P. et al. FinnGen provides genetic insights from a well-phenotyped isolated population. Nature 613, 508–518 (2023). doi.org/10.1038/s41586-022-05473-8
Gamete banks should add disclaimers to donor profiles
Non-medical information from sperm and egg donors that has not been verified, such as personality traits and sporting ability, should carry a disclaimer.
This is the recommendation of an opinion piece (1) that concludes warning labels would protect gamete banks from lawsuits, from the ‘unjustified expectations’ of recipients, and spare them the time and cost that would be involved in checking every detail in donor profiles.
Writing in Human Reproduction, Guido Pennings suggests the measure would ensure donors take responsibility if it emerged that any self-reported information were false. Professor Pennings, from Ghent University in Belgium, advises clinics to put warning labels on non-medical details shared with would-be parents. This is because of cases where donors have lied about their backgrounds (2).
Although the number brought to court is low, these incidents of fraud have led parents of donor-conceived children to take action against clinics, says Professor Pennings. The expert in ethics and bioethics warns this trend could rise as more children learn who their biological parents really are, such as via genealogy databases.
Few gamete banks currently mention on their websites whether donor profiles have been verified. If the gamete bank knows the information is false but takes no further action then they could be found negligent. Or the donors should be held liable if they intentionally withhold information or lie. Yet, in the opinion article, Professor Pennings says most cases are not simple and other ethical issues have to be considered such as reproductive harm and welfare of the child.
People who use gamete banks select their donor based not only on their medical history but also on athletic ability, intelligence, personality traits and other details contained in the donor profile which are largely self-reported. Patients assume gamete facilities are responsible for ensuring these background profiles are as accurate as the donor’s medical details. In addition, some people who use gamete banks believe their offspring are guaranteed to inherit these qualities despite the odds being weak.
As such, the potential exists for gamete recipients to claim they have suffered harm, for example if the donor had falsified their religion or the child does not have the characteristics that the donor claims to possess.
Education and criminal history are two key characteristics of the donor, and these are explored in detail by Professor Pennings. Recipients regard education as important when making their selection, and he says qualification certificates are ‘easy to obtain in most countries’. However, Professor Pennings points out that asking donors for this evidence could demonstrate mistrust by the gamete bank. As for criminal record checks, some clinics already require these but the predicament is where to draw the line. Professor Pennings poses the question: “What kind of crime does the candidate donor have to have committed to be disqualified?”
All these issues relating to the donor profile leave banks with a clear dilemma, writes Professor Pennings. They could perform extra checks and demand donors back up their claims with evidence such as criminal record or education certificates.
However, he argues ‘no gamete bank can guarantee that all information provided by the donor is true or complete’ and that attempting to ask for more proof would potentially alienate donors. What’s more, the increased cost of extra control measures would, says Professor Pennings, push more recipients to find donors via social media and connection websites.
Another approach would be for gamete banks to limit the donor profile to details that are easy to verify such as formal education, criminal record and height. The flaw in this approach, writes Professor Pennings, is that banks are commercial organisations. For this reason, they want to provide information that interests their clients and ‘that list is likely to include characteristics that are not easily verifiable’.
Instead, the solution that he puts forward is for clinics to divide the donor profile into two sections – verified and non-verified – and label them accordingly. Generally, banks provide a basic profile and an extended one.
Professor Pennings suggests the non-verified disclaimer could apply to the extended profile, which provides a more detailed statement from the donor such as personality type, and may contain a handwritten message and voice recording. On this basis, the donor – not the clinic – would be responsible, he adds.
A key question left unanswered by Professor Pennings is: what details exactly should be included in the donor profile? Despite leaving this open to debate, he does say that ‘cultural beliefs about heritability’ and the desire of recipients to have information about ‘certain traits’ are the main determinants of what is currently contained in the personal profile.
Of course, if all donors provided candid and complete information then measures such as warning labels would not be necessary. However, evidence cited by Professor Pennings shows that most people on dating sites lie about some aspect of their life (3) as do blood donors. There’s no reason for gamete donors to differ although no figures exist on how many withhold information or lie.
In reality, most untruths will go ‘undetected and cause no harm’ but, to err on the side of caution, Professor Pennings says: “By adding the disclaimer, the gamete banks would avoid liability and recipients could temper their expectations.”
References:
1 Guido Pennings, Should a gamete bank verify the non-medical information provided by a donor?, Human Reproduction, 2024;, deae004, https://doi.org/10.1093/humrep/deae004
2 Heled Y et al. Righting a reproductive wrong: a statutory tort solution to misrepresentation by reproductive tissue providers. Houston Law Review 2022; vol 60; 1-50; https://houstonlawreview.org/article/55520-righting-a-reproductive-wrong-a-statutory-tort-solution-to-misrepresentation-by-reproductive-tissue-providers
3 Toma CL at al. Separating Fact From Fiction: An Examination of Deceptive Self-Presentation in Online Dating Profiles. Personality and Social Psychology Bulletin; 34(8); 1023-1036; https://doi.org/10.1177/0146167208318067
Dr Aleksej Stevanovic
During a Campus meeting in March on environmental quality in the lab, Aleksej Stevanovic gave a presentation on temperature control. Here Dr Stevanovic, junior deputy coordinator SIG Safety and Quality in IVF, talks to Sophie Goodchild from Focus on Reproduction including about how he addressed issues in his own clinic.
Policymakers, healthcare professionals and employers must address declining global fertility rates now, say experts
Fertility care should be a key focus of government strategies to address declining global fertility rates, say experts. The International Federation of Fertility Societies (IFFS) warns in a new consensus document (1) of ‘major disparities’ in access to ART and to other types of support for people who want families. The authors say policies to improve fertility care are essential to manage the ‘major societal and economic implications’ of a dramatic population decrease, as observed in many countries.
Data included in the analysis suggest most countries will soon have an average number of children far below the replacement level, a trend which the IFFS says is partly the consequence of family planning policies to restrict population growth. By 2050, the total fertility rate (TFR) is expected to drop below 2.1 children per woman in 77% of predominantly high-income countries; and in 93% of all countries by 2100. Excluding migration, populations could decline in many nations by more than half from 2017 to the end of this century, according to the authors who carried out a narrative review of literature.
In a call to action, the document makes a series of recommendations around awareness, human rights, and access to care. The right of all individuals to have a child if desired must be recognised; educational programmes should focus more on family building and infertility prevention; and public and insurance funding of fertility care should be increased and coverage expanded to individuals and same-sex couples, says the IFFS.
While the priority for many countries has been on reducing their populations, concerns have been growing around falling fertility rates. A landmark paper (2) brought declining sperm counts to international attention in 2017, and again in 2022 when the updated study showed this trend was continuing. Elsewhere, some governments have been taking action to boost fertility rates including in France where president Emmanuel Macron proposed free fertility testing for anyone aged 25 years.
The IFFS says their report represents the first attempt to describe the huge inequalities in accessing fertility care specifically in the context of underpopulation concerns. Literature searches were performed up to September 2023 by ‘global leaders’ in the field of fertility from countries including the UK, US and Australia. They were invited by the IFFS to prepare the review document for which full consensus was reached at a 2-day meeting in May 2022. Topics covered by the document include infertility prevalence, awareness and prevention; and how to work towards equitable access to fertility care.
Writing in the paper, the authors point out that infertility is preventable and that there have been significant advancements in fertility treatments over the past three decades, progress which benefits not only heterosexual couples but also same sex and those from LGBTQ+ communities.
However, the consensus document concludes that fertility care is unaffordable for many people around the world and that “many barriers remain for the inclusion of fertility care in reproductive health policies”. The authors cite IFFS surveillance data (3) showing that less than half of those countries who provided information to the organisation offer any financial support for ART, and only 20% reimburse in full. An urgent need also exists to develop less expensive ART that is accessible for all especially in low to middle income countries. “The child who results from fertility care represents a strong economic benefit for society,” add the authors.
In addition to addressing funding and access, policymakers are urged by the IFFS to develop and implement policies that reduce environmental and lifestyle-related risk factors for infertility. Air pollution and the proliferation of harmful and poorly regulated chemicals are increasing, say the review authors, in addition to the negative effect from sexually transmitted infections, obesity, poor nutrition and lifestyle factors such as smoking and excessive alcohol intake.
Other issues affecting the TFR decline include discrimination against women, inadequate support of working parents, and people delaying parenthood. On this basis, the IFFS says that an increasing number of countries have introduced family-friendly policies such as extended pregnancy leave and compensation for childcare, but the amount spent varies between nations.
Overall, the message from the IFFS report is that solutions to addressing declining fertility rates must reflect the fact that people use diverse ways to build their families, from IVF to adoption. As such, they need support to achieve their individual fertility goals.
Alongside this research, the IFFS has launched the More Joy campaign for fairer access to fertility care and to prevent infertility risk factors. Translated into 15 languages, the global initiative istargeted at policymakers, companies, healthcare professionals with the aim of persuading them to make fertility care a priority and to educate patients.
In an interview with Focus on Reproduction, IFFS president and ESHRE member Edgar Mocanu said comprehensive reforms were needed now.
Professor Mocanu, from the Rotunda Hospital in Ireland, said: “Policymakers need to do more to reverse this downward trend. Otherwise, the impact of underpopulation on societies and economies could be considerable.
“Family building must become part of family planning, and everyone who wishes to achieve their parenting goal must get the support they need.”
References:
1 Fauser et al. Declining global fertility rates and the implications for family planning and family building: an IFFS consensus document based on a narrative review of the literature. Hum Reprod Update March-April 2024; Vol 30 (2); 153–173; https://doi.org/10.1093/humupd/dmad028
2 Levine et al. Temporal trends in sperm count: a systematic review and meta-regression analysis of samples collected globally in the 20th and 21st centuries. Hum Reprod Update, Vol 29 (2); March-April 2023; 157–176; https://doi.org/10.1093/humupd/dmac035
3 International Federation of Fertility Societies’ Surveillance (IFFS) 2022: Global Trends in Reproductive Policy and Practice, 9th Edition. Global Reproductive Health; 7(3):p e58, Autumn 2022; DOI: 10.1097/GRH.0000000000000058
Increased risk of overweight in teenage years for boys born after frozen embryo transfer
Large national registry-based study finds odds of overweight in adolescence are greater for boys born following FET than those born after fresh embryo transfer or natural conception.
Boys born after frozen embryo transfer (FET) have higher odds of overweight in adolescence than those born after fresh embryo transfer or natural conception, the longest follow-up to-date on the growth of children conceived by FET has concluded.(1)
In contrast, girls born after FET were found to have slightly lower odds of overweight than those conceived naturally.
With FET making up a third of treatment cycles in Europe and rising, the collection of long-term safety data is of the utmost importance, note the authors.
Thus, they recommend that future studies explore whether boys born after FET are at greater risk of overweight and cardiometabolic disease in adulthood.
Importantly, the embryo transfers were mainly performed at the cleavage stage and slow freezing was used; thus, the findings may not apply to blastocyst transfers and vitrification.
Children born after FET are known to have higher mean birthweights and a higher risk of large-for-gestational age (LGA), which raises questions about possible growth differences later in childhood.
However, previous studies on their growth have produced some conflicting results and there is a lack of data on adolescence.
The authors of the new cohort study used data from national population-based registers in Finland, where schoolchildren are offered annual growth checks, to address this.
They compared the proportions and odds of overweight in singletons born after FET (n=1,825), fresh embryo transfer (n=2,933) and natural conception (NC, n=31,136) between 1995 and 2006.
Mean weights, heights and BMIs were compared between the groups each year between the ages of 7 and 18. The results were adjusted for birth year, preterm birth, maternal age, parity and socioeconomic status.
Birth register data showed that children born after FET were heavier, on average, at birth, than those born after fresh transfers but not NC. Boys born after FET were more likely to be LGA than boys born after fresh embryo transfer or NC. Similarly, girls born after FET were more likely to be LGA than girls born following fresh embryo transfer but not those born after NC.
Analysis of the growth data showed that boys born after FET tended to be heavier in adolescence. The boys in the FET group had significantly higher odds of overweight (BMI ≥ 25) between ages 14 and 16 than the boys in fresh embryo transfer group and between ages 15 and 16 than the boys in the NC group.
For all ages combined, the odds of overweight were higher for boys in the FET group compared to those in the fresh embryo transfer and the NC group (adjusted odds ratio (AOR): 1.14, 95% CI 1.02–1.27 and 1.08, 95% CI 0.99–1.18, respectively).
The mean proportion of overweight was 28% for boys in the FET group, 22% in the fresh embryo group and 26% in the NC group.
The authors state: ‘The main finding in this register-based study is that towards the end of follow-up, FET boys were heavier with a higher BMI and increased odds of overweight compared to fresh ET. There were no significant differences in height between FET and fresh ET boys.’
The picture was different for girls. Height, weight and BMI were similar between the three groups of girls. However, the girls in the FET group had slightly decreased odds of overweight (all ages combined AOR 0.89, 95% CI 0.8-0.99) than the girls in the NC group.
The authors suggest that the differences in growth between the FET, fresh transfer and NC groups may be due to epigenetic changes that are induced by embryo freezing or the hormonal environment in the uterus at embryo transfer.
As to why the pattern of overweight differs between the sexes, the authors say the association between LGA and FET – and so the likelihood of overweight in later years – may be stronger for boys.
They note that their results differ from those of a recent large population-based study which found no differences in the height and weight of children born after ART (including FET ) and NC at age 17(2). They suggest this is because they analysed data for the boys and girls separately, while the earlier study analysed both sexes together, adjusting for sex.
The main limitation of the study was the inability to adjust for parental weight and height. Growth data was not available for all the children at each age and so the results at the start and end of the follow-up period should be regarded with caution.
The authors note that all mean height and weight measurements were well within the normal growth range and the clinical relevance of the small growth differences remains unknown.
However, the higher risk of overweight in boys born after FET could ‘be indicative of an increased risk of overweight or obesity in adulthood, as well as increased risk of cardiovascular disease, diabetes, musculoskeletal disorders and some cancers’ and thus further research is warranted.(3)
They end on a positive note, saying: ‘The lack of significant differences in height after FET and fresh embryo transfer offers reassurance of the safety and feasibility of FET in the treatment of infertility.’
1. Terho AM, Tiitinen A, Salo J, Martikainen H, Gissler M, Pelkonen S. Growth of singletons born after frozen embryo transfer until early adulthood: a Finnish register study. Human Reproduction. 2024 Jan 4;dead264.
2. Magnus MC, Wilcox AJ, Fadum EA, Gjessing HK, Opdahl S, Juliusson PB, et al. Growth in children conceived by ART. Human Reproduction. 2021 Mar 18;36(4):1074–82.
3. WHO. WHO Fact Sheet Overweight and Obesity. 2022. https://www.who.int/news-room/fact-sheets/detail/obesity-and-overweight
Patient Comfort in IVF: Exploring the Efficacy of Virtual Reality in Oocyte Retrieval
Oocyte retrieval, a pivotal step in the in vitro fertilization (IVF) process, involves the collection of mature oocytes from the ovaries through ultrasound-directed transvaginal follicle aspiration. Despite its efficacy, this procedure often induces pain and stress, necessitating exploration into various pain relief options.
Conscious sedation, a widely used approach involving a combination of sedatives and local anesthetics, allows patients to remain conscious while minimizing discomfort during the procedure. It has minimal side effects and is low risk, facilitating a swift return to normal activities and early discharge. However, some patients still endure pain and discomfort, leading to the investigation of additional techniques for enhanced comfort and satisfaction. Moreover, it is recognized that a patient’s psychological state has an influence on sedation. Patients experiencing anxiety may require higher sedative doses, posing challenges for clinicians. Recognising the influence of a patient’s mental health, research on non-pharmacological methods to reduce anxiety and improve sedation experience expanding.
Sedation by virtual reality (VR) has been emerging as an innovative method for relieving patients’ pain and anxiety throughout medical procedures. This transformative digital therapy employs three-dimensional multi-sensory immersion, combining clinical hypnotherapy and integrative therapeutics. By stimulating multiple human senses, VR systems create an immersive experience, fostering a feeling of presence in the virtual world. Although the positive psychological impact of VR on sedation outcomes is increasingly being acknowledged, limited research has explored the benefits of VR, specifically hypnosis, in the field of fertility during surgical interventions such as oocyte retrieval.
The preliminary data collected aimed to investigate the anxiety-reducing effects and patient satisfaction associated with VR during oocyte retrieval, focusing on its potential as an alternative to traditional analgesics.
A total of forty patients undergoing oocyte retrieval consented to participate in the VR experience, facilitated through an immersion headset. The VR session commenced, lasting a maximum of 20 minutes. Low doses of fentanyl (75mcg) and midazolam (1mg) were administered as needed, with sedation adjusted to ensure patient comfort. Subsequently, each participant completed a comprehensive questionnaire before discharge, providing insights into pain perception, overall experience, and satisfaction levels.
Results from the questionnaire suggest this non-pharmacological approach is effective and has a positive impact on patient well-being. Notably, 63% of participants reported a high level of immersion during the VR session, while, 95% of patients noted an additional level of comfort during the oocyte retrieval procedure. The most striking statistic was the satisfaction category, with 98% expressing high levels of contentment with the VR session.
A subgroup analysis involved patients with prior oocyte retrieval experience. In this cohort, 93% declared that VR significantly improved their comfort levels during the procedure. Additionally, an equivalent percentage acknowledged an overall enhancement in their experience of the oocyte retrieval process.
In conclusion, the integration of VR in a clinical setting emerges as a promising approach complementing routine sedation, with a notable level of patient adherence. The high satisfaction reported by participants underscores its potential as an easily implementable solution within a clinical setting, offering tangible improvements in patient comfort during oocyte retrieval. These results warrant further investigation through prospective multi-centre studies involving larger cohorts. Such studies are essential to solidify the efficacy of pain management using VR devices in reproductive medicine practice. The future integration of these innovative technologies holds the promise of revolutionizing and elevating the overall patient experience in fertility treatments.
Exploring why ovarian stimulation with highly purified HMG leads to lower serum progesterone than recombinant FSH
Serum progesterone is lower in ovarian stimulation with highly purified HMG (hp-HMG) than recombinant FSH (r-FSH) owing to differences in follicular steroidogenesis, an RCT has found. (1)
This has led the authors to suggest that clinics consider using hp-HMG rather than r-FSH, particularly in patients at risk of having high progesterone levels at the end of the follicular phase, when a fresh embryo transfer is planned.
Elevated progesterone levels at the end of ovarian stimulation are associated with lower clinical outcomes in fresh IVF cycles. However, some studies have found that serum progesterone is lower on the day of triggering when hp-HMG is used for ovarian stimulation rather than recombinant FSH (r-FSH).(2,3)
But the reason has not been clear. Is it because there is a lower ovarian response in hp-HMG cycles? Or is it because the different stimulation protocols promote different pathways of follicular steroidogenesis?
To explore this, the study’s authors prospectively compared the effect of hp-HMG and r-FSH on serum concentrations of progesterone and other follicular steroids.
The single-centre, open-label, prospective randomised study involved 112 oocyte donors undergoing ovarian stimulation with GnRH antagonists and 225IU/day of r-FSH or hp-HMG. Baseline clinical characteristics between both groups were comparable in terms of age, BMI and AMH levels.
The ovarian response was similar in both groups (17.5 oocytes, on average, with r-FSH, vs 16.5 with hp-HMG).
But there were clear differences in the endocrine profiles in the second half of the stimulation cycles.
Serum progesterone was significantly higher in the r-FSH group than in the hp-HMG group on day of trigger (0.68 ng/ml vs 0.46 ng/ml ) and on stimulation days 6 and 8. Plus, the progesterone:pregnenolone ratio was significantly increased in the r-FSH group on the day of trigger and day 8.
Serum androstenodione was higher in the hp-HMG group than in the r-FSH group on the day of trigger (3.0 ng/ml vs 2.4 ng/ml) and on day 8. And the androstenodione:pregnenolone ratio was significantly higher in the hp-HMG group on the day of trigger and days 6 and 8.
There were no other significant differences between groups.
The authors also analysed the follicular fluid. This showed oestradiol, FSH, LH, dehydroepiandrosterone, androstenodione and testosterone to be significantly higher in the hp-HMG than in the r-FSH group.
No differences were observed for oestrone, 17-OH-progesterone, pregnenolone and progesterone. (The authors further hypothesised that the excess progesterone produced in the FSH cycles may be released or leaked into the circulation, rather than remaining in the follicles.)
The finding that the different endocrine profiles occurred independent of ovarian response suggests that r-FSH and hp-HMG regulate follicular steroidogenesis differently, say the authors.
hp-HMG seems to enhance the conversion of pregnenolone to androstenodione, leading to lower serum progesterone at the end of the cycle.
In contrast, r-FSH promotes the conversion of pregnenolone to progesterone, leading to higher follicular phase progesterone levels.
So, how can this difference be explained?
The authors say it is likely that in the absence of LH activity (from hp-HMG), pregnenolone is mostly converted to progesterone with no further metabolism, ‘an event that is even stronger when recombinant FSH is used instead of urinary FSH’ found in hp-HMG.
They go on to state: ‘Regardless of the mechanism involved, it is known that high serum progesterone levels have a direct impact on the endometrium, which may impair its receptivity.
‘According to the observations of a large meta-analysis, the serum progesterone levels needed to impair cycle outcome may differ according to ovarian response, being lower in poor responders and higher in high responders.’(4)
The authors, who received funding from Roche for the immunoassays used to determine the hormone levels, acknowledge that all the women included in their study were young, had a normal BMI and ovarian reserve and were not infertile and so the findings may be different in other patient populations.
Moreover, the immunoassays are subject to intra-assay variations that could have influenced the results.
Nevertheless, they conclude that although serum progesterone levels observed on the day of trigger ‘would not suggest a clinical problem’, their findings should be considered when choosing an ovarian stimulation protocol.
- Bosch E, Alamá P, Romero JL, Marí M, Labarta E, Pellicer A. Serum progesterone is lower in ovarian stimulation with highly purified HMG compared to recombinant FSH owing to a different regulation of follicular steroidogenesis: a randomized controlled trial. Human Reproduction. 2023 00(0), 1–10. doi.org/10.1093/humrep/dead251
- Andersen AN, Devroey P, Arce JC, for the MERIT Group. Clinical outcome following stimulation with highly purified hMG or recombinant FSH in patients undergoing IVF: a randomized assessor-blind controlled trial. Human Reproduction. 2006 Dec 1;21(12):3217–27. doi.org/10.1093/humrep/del284
- Bosch E, Vidal C, Labarta E, Simon C, Remohi J, Pellicer A. Highly purified hMG versus recombinant FSH in ovarian hyperstimulation with GnRH antagonists—a randomized study. Human Reproduction. 2008 Oct 1;23(10):2346–51. doi.org/10.1093/humrep/den220
- Venetis CA, Kolibianakis EM, Bosdou JK, Tarlatzis BC. Progesterone elevation and probability of pregnancy after IVF: a systematic review and meta-analysis of over 60 000 cycles. Human Reproduction Update. 2013 Sep 1;19(5):433–57. doi.org/10.1093/humupd/dmt014
New data show infertility cases related to PCOS have more than doubled over two decades
The first comprehensive analysis of infertility related to PCOS has shown that cases among women of reproductive age rose from 6 million in 1990 to 12.13m in 2019 across more than 200 countries and regions; and ‘increased sharply’ in most parts of the world (1).
The findings, say the authors, underline the need for more effective health interventions and ‘efficient preventative and managerial strategies’. Indeed, they urge that weight control should be used to reduce this trend especially in regions with high levels of social and economic development where the burden of PCOS-related infertility was found to be the greatest.
PCOS is the most common cause of anovulatory infertility, affecting up to 80% of women who do not ovulate during a menstrual cycle. However, no comprehensive and detailed epidemiological estimates have been reported of PCOS-related infertility in reproductive women (15 to 49 years) by age and socio-demographic index (SDI), at the global, regional, and national level.
Now, say the authors, their global, regional and national analysis based on up-to-date data across 204 countries and regions provides comprehensive evidence of the impact of PCOS on types of fertility including primary and secondary.
The authors used the Global Burden of Disease 2019 study (GBD 2019) which includes information from sources such as censuses, medical registries and demographic surveillance (2). The GBD 2019 categorised the 204 countries into five SDI quintiles (low, low-middle, middle, high-middle, and high) based on the SDI value of each nation in 2019; and grouped the countries into 21 regions and 5 super-regions including central Europe, East Asia and high-income North America.
The National Institutes of Health (NIH) definition was used by the GBD 2019 for the PCOS diagnostic criteria. Infertility was defined as the inability to establish a clinical pregnancy after 12 months or more of unprotected sexual intercourse. Primary infertility was defined as a woman who had not been pregnant before; and secondary as a woman who had conceived and successfully given birth yet was unable to do so subsequently. The authors do not refer to women who have conceived yet miscarried in the definitions of infertility which they use.
The number, rates per 100 000 persons, and average annual percentage changes (AAPCs) of prevalence and years lived with disability (YLD) were estimated globally, regionally, and nationally. The YLDs of infertility attributable to PCOS were calculated by multiplying primary infertility prevalence by its disability weight (0.008) and secondary infertility prevalence by its disability weight (0.005).
Results showed an upward trend overall in the global age-standardized prevalence rates (ASPRs) and YLD rates (global ASPR=223.50/100 000 persons in 1990 vs 308.25/100 000 in 2019; YLD rate=35.20 thousand in 1990 vs 69.70 thousand in 2019).
The burden of infertility attributable to PCOS – based on ASPR and YLD rates – was significantly greater overall in the high SDI region than in the other four SDI regions. The highest annual increases in ASPRs and age-standardized YLD rates were observed in the middle and low middle quintiles. This latter finding, say the authors, might be explained by the fact the disability-adjusted life years (DALY) related to obesity was on the increase from 1990 to 2019 in the middle and low-middle SDI regions but was declining in the high and high-middle SDI regions.
In 2019, high-income Asia Pacific had the greatest regional ASPR and age-standardized YLD rate of infertility followed by Western Europe and high-income North America; and nationally Italy had the greatest ASPR and age-standardised YLD.
The burden of infertility attributable to PCOS was lowest in the age groups 15 to 19 and 45 to 49 years and was stable in women aged 20–44 years, a finding which the authors say may result from the low prevalence of PCOS among women aged 45 to 49 years.
Despite the robust dataset underpinning this study, the authors acknowledge that some countries could only provide limited data which may result in an ‘underestimation of the burden of infertility attributable to PCOS’.In addition, they say the diagnostic criteria of PCOS are constantly changing, which may ‘induce bias of infertility attributable to PCOS’.
Other limitations include detection bias which would lead to a higher prevalence of PCOS and PCOS-related infertility in developed countries with comprehensive health systems and ‘greater willingness of the populace to seek medical attention’. As such, the authors say that the allocation of health resources in areas of low prevalence should not be ignored.
Recent PCOS guidelines highlighted the importance of preventing weight gain (3). This recommendation is echoed by the authors of this study who conclude that the rapid global increase in obesity may be at least partially linked to the burden of PCOS-related infertility. What also needs to be addressed, they add, is that IVF remains ‘inaccessible and underfunded’ even in high income countries where PCOS is more likely to be diagnosed.
References:
1 Xingyu Liu, Jinjin Zhang, Shixuan Wang, Global, regional, and national burden of infertility attributable to PCOS, 1990–2019; Hum Reprod Jan 2024, vol 39 (1); 108–118; https://doi.org/10.1093/humrep/dead241
2 Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019; The Lancet Open October 2020; DOI:https://doi.org/10.1016/S0140-6736(20)30925-9
3 Helena J Teede HJ et al. Recommendations from the 2023 International Evidence-based Guideline for the Assessment and Management of Polycystic Ovary Syndrome. Hum Reprod Vol 38(9) September 2023; Pages 1655–1679; https://doi.org/10.1093/humrep/dead156
Authors of a cohort study say don’t use ICSI for non-male factor infertility in PGT-A
ICSI should not be used in PGT-A – unless indicated for male infertility factor ICSI – according to the authors of a large retrospective cohort study (1) which has found that the fertility treatment offers no benefit over conventional IVF (cIVF) for embryo quality and live birth rates (LBRs).
Based on more than 30,000 PGT-A cycles carried out in the USA for non-male factor infertility, the main findings show that embryos suitable for transfer and LBRs ‘are not significantly different’ in cIVF vs ICSI. In addition, ICSI did not improve secondary outcomes such as gestational age at delivery, birth weight and unexplained infertility.
The study which used data from the Society for Assisted Reproductive Technology Clinic Outcome Reporting System (SARS CORS) adds to the debate around the overuse of ICSI outside its primary indication for male infertility. While acknowledging that ICSI has enabled ‘countless’ infertile men to have genetically-related children, the authors say the fertility treatment is ‘not without its limitations’ including increased cost and controversy over adverse neonatal outcomes.
The use of ICSI for PGT-A has arisen out of concerns that results could be affected by contamination from residual cumulus cells and from surplus sperm attached to the zona pellucida because of cIVF. On this basis, ESHRE good practice recommendations have suggested ICSI is preferable for PGT (2) as have those from the American Society of Reproductive Medicine (ASRM) (3).
However, the authors of this retrospective cohort study say that advancements in PGT-A mean genomic contamination has been ‘drastically reduced’. They say this calls into question ‘the necessity of ICSI for PGT-A tested embryos ’, a conclusion which has been backed up by other studies. Moreover, the authors argue that the use cIVF for non-male factor PGT-A cycles could lead to a decrease in costs and in ‘embryology labor’ for fertility clinics. The results also question clinics’ rising use of ICSI for unexplained fertility in the belief that couples will benefit by increasing their chance of having a baby.
The authors used data from the SART CORS database) relating to all cIVF/ICSI cycles involving PGT-A from January 2014 to December 2017. SART CORS holds information from fertility clinics in the USA who are SART members. All frozen thawed embryo transfer (FET) cycles linked to PGT-A cycles were also evaluated for LBRs.
The primary outcomes were percentage of embryos suitable for transfer and LBRs. Secondary outcomes included subgroup analysis for embryos suitable for transfer on cycles from patients aged 35 years (y/o) or above vs those aged under 35 years; 6 or fewer oocytes retrieved vs more than 6; and cycles with the diagnosis of unexplained infertility. Additionally, gestational age at delivery and birthweight between cIVF and ICSI were evaluated.
Additional secondary outcomes included rates of pregnancy loss, average gestational age at delivery, birthweight, and sub-analysis of first FET cycles.
Exclusion criteria included PGT cycles where either parent was a carrier for a genetic disease, use of frozen oocytes and cycles with more than 10 embryos biopsied; and potential confounding variables included maternal age, maximum FSH level and number of oocytes retrieved.
A total of 30,446 non-male factor PGT-A cycles (n=4,867 cIVF cycles; n=25,579 ICSI) met the inclusion criteria. Results showed no significant differences in rate of embryos suitable for transfer between cIVF vs ICSI (41.6% vs 42.5% respectively, p=0.12) or within the patient subgroups (≥35 y/o=35.7% vs 36.5%, p=0.25; <35 y/o=57.6% vs 58.6%, p=0.21; ≤6 oocytes retrieved=32.9% vs 35.3%, p=0.12; >6 oocytes retrieved=43.9% vs 44.2%, p=0.66; and unexplained infertility=46.4% vs 48.8%, p=0.09).
Analysis of single FET (n=3,412 IVF; n=16,358 ICSI) found no significant differences for LBRs (50.1% vs 50.8% respectively, p=0.51) and pregnancy loss rates (16.6% vs 15.5, p=0.11); and sub-analysis of first FET transfers only in cIVF vs ICSI revealed a similar trend for LBRs (53.4% vs 53%, p=0.78) and pregnancy loss rates (15.7% vs 15.5%, p=0.84).
In addition, no significant differences were found in cIVF vs ICSI for gestational age in days (265.8 vs 265.6, p=0.73) and birth weight in grams at delivery (3,376.7 vs 3,363.5, p value=0.42).
Limitations of the study include the fact data may be biased towards larger centres, and that ICSI requires technical skill which may differ among embryologists and between centres.
Several areas of research were not covered by this SART CORs analysis: these are recommended for further study by the authors. In their paper, they write that evaluation of the incidence of mosaic embryos is important ‘given the ability’ for these embryos to lead to live births; and suggest that evidence is needed on whether ICSI decreases paternal contamination during PGT-A cycles.
References:
1 Tozour J, Arnott A, Akerman M, Sung L, Vintzileos A and Fritz R. Comparison of Outcomes Between Intracytoplasmic Sperm Injection and In Vitro Fertilization with Pre-implantation Genetic Testing for Aneuploidy, Analysis of SART CORS Data. Fertility and Sterility (2024); https://doi.org/10.1016/j.fertnstert.2023.12.041
2 Georgia Kokkali et al. ESHRE PGT Consortium and SIG-Embryology Biopsy Working Group. ESHRE PGT Consortium and SIG Embryology good practice recommendations for polar body and embryo biopsy for PGT. HR Open 2020 (3); https://doi.org/10.1093/hropen/hoaa020
3 Intracytoplasmic sperm injection (ICSI) for non–male factor indications: a committee opinion Practice Committees of the American Society for Reproductive Medicine and the Society for Assisted Reproductive Technology. Fert and Steril 2020; vol 114 (2); https://doi.org/10.1016/j.fertnstert.2020.05.032
Poor-quality blastocysts result in lower live birth rate – but do not lead to more adverse perinatal outcomes
In the era of single embryo transfer in clinical practice, the focus is on selecting the best embryo for transfer and low-quality blastocysts are routinely discarded by some clinics.
While it is known that low-quality blastocysts can lead to live births, the relatively small sample sizes and single-centre design of existing studies mean there is limited information on their potential. Even less is known about the impact of low-grade blastocysts on perinatal outcomes.
The results of a new study provide some clarity, along with a reassuring message for women.(1)
IVF patients should be informed that although low-quality embryos result in a lower LBR, it’s still ‘reasonable’ – and there’s no increase in the risk of adverse perinatal outcomes, say the authors.
The multi-centre, multi-national retrospective cohort study involved 10,018 women undergoing 10,964 single blastocyst transfer cycles in 14 clinics in Australia, China and New Zealand between 2009 and 2020.
The morphology and development of the inner cell mass (ICM) and trophectoderm (TE) of each blastocyst was graded ‘A’, ‘B’ or ‘C’, using the Gardner system.
Blastocysts with an A or B in both ICM and TE were classed as being of good quality (AA, AB, or BA; n=4,386). Those with a B in both ICM and TE were classed as moderate-grade (BB; n=3,735) and those with a C in either ICM or TE as low-grade (AC, CA, BC, CB, CC; n=2,843).
Day 5, 6 and 7 blastocysts were included, with the majority being Day 5. (90.7% of the good quality blastocysts were Day 5, vs 83.2% of the moderate quality blastocysts and 61.1% of the low-quality blastocysts.)
The LBR for the good-quality blastocyst group was 44.4%. This compares to a LBR of 38.6% (adjusted odds ratio (aOR ) 0.70, 95% CI 0.62–0.77) for the moderate-quality group and 30.2% (aOR 0.48, 95% CI 0.41–0.55) for the low-quality blastocysts.
For the very low-quality blastocysts (CC only), the LBR was 13.7%. This is close to the 16.7% LBR for CC blastocysts in another study.(2)
The results also suggest that the quality of the ICM is more important in achieving a live birth than the quality of the TE.
As might be expected, the LBR was lower in older women but it remained over 15% with low-grade blastocysts, even in the oldest quintile (≥38 years). This is ‘still high enough to justify the transfer of low-grade blastocysts,’ say the authors.
The results of the analysis of the association between blastocyst quality and perinatal outcomes were also reassuring.
The analysis of 4,132 singleton births found there was no significant difference between the low and good-grade blastocysts in any of the parameters studied (pre-term birth, birthweight Z-score, rates of very low birth weight, low birth weight, high birth weight, small for gestational age, large for gestational age).
In addition, perinatal outcomes were comparable between Day 5 and Day 6 low-grade blastocysts.
Finally, better-quality blastocysts were associated with higher clinical pregnancy rates but rates of pregnancy loss were similar in low, moderate and good-grade blastocysts.
Strengths of the study include its large sample size. And, by restricting the study population to single blastocyst transfers, the authors removed the need to trace the outcomes of individual embryos.
Among the limitations are the small size of some of the low-grade sub-groups and differences in blastocyst grading within, and between, clinics. Moreover, although the results were adjusted for confounding factors (institution, fresh/frozen transfer, female age, blastocyst developmental stage, blastocyst age and, in the case of perinatal outcomes, infant sex), the retrospective nature of the design means that some residual confounding could not be avoided.
The authors say that while low-grade blastocysts did not survive cryopreservation well in the past, vitrification has led to better preservation and so better reproductive outcomes.
Thus, the transfer of low-quality blastocysts could allow couples who do not have any good or moderate-grade blastocysts to avoid the delay, cost and psychological burden associated with starting a new stimulation cycle.
It will be important, however, to determine the added value of transferring low-grade blastocysts – especially for women with multiple failed transfers with good-quality blastocysts, say the authors.
They conclude that women undergoing IVF treatment should be informed that low-grade blastocysts result in lower, but ‘reasonable’, live birth rates. This is achieved without increasing the risk of adverse perinatal outcomes.
Indeed, even very low-quality blastocysts (CC) can result in live births. The perinatal outcomes of such embryos need to be investigated in a larger cohort, however, say the authors.
Suggestions for future research include developing criteria for embryos that should not be transferred. Other foetal outcomes and pregnancy complications, such as placentation, pre-eclampsia and hypertensive disorders, haemorrhage and placenta previa, should also be studied. The long-term follow-up of childhood outcomes is also required, say the authors.
1. Zou H, Kemper JM, Hammond ER, Xu F, Liu G, Xue L, et al. Blastocyst quality and reproductive and perinatal outcomes: a multinational multicentre observational study. Human Reproduction. 2023 Dec 1;38(12):2391–9. doi.org/10.1093/humrep/dead212
2. Li M, Yin M, Wu L, Yan Z, Lyu Q, Yan Z, et al. Pregnancy and neonatal outcomes of morphologically grade CC blastocysts: are they of clinical value? Arch Gynecol Obstet. 2020 Dec 1;302(6):1511–21. doi.org/10.1007/s00404-020-05741-w
